Cytokines, which have long been known to regulate immune function and hematopoiesis, have recently been shown to exert powerful effects on neural gene expression, proliferation, and survival. Indeed the boundaries between peptides classified as cytokines and as neurotrophic factors has been increasingly blurred. For example, cytokines such as interleukin-1=DF (IL-1=DF) which act in the periphery to modulate the immune response, act within the hypothalamus to regulate overall organismic adaptations to infection, inflammation, and stress. Other cytokines, such as leukemia inhibitory factor (LIF), appear to be involved in the adaptation of the nervous system to injury, and are closely related to factors involved in neuronal survival and phenotype determination. Little is known to date about the molecular mechanisms by which cytokines regulate transcription of neural genes, and even less is known about the interactions among cytokine and neurotransmitter signaling pathways. The proenkephalin gene, which encodes the opioid peptides met- and leu-enkephalin, has served as an important model of transcriptional regulation in the nervous system; therefore much is known about proenkephalin gene structure and regulation. Because proenkephalin gene expression is regulated not only by neurotransmitters and drugs of abuse, but also by multiple cytokines, including both IL-1=DF and LIF, we propose to use the proenkephalin gene as = a model to elucidate the molecular actions of these representative and physiologically significant cytokines in the nervous system. We propose to use primary cultures of glia and hypothalamic neurons and the hypothalamus in intact animals, including transgenic mice, to study cytokine signalling pathways, their interactions with neurotransmitter signaling pathways, and their modulation by opioids. The resulting information should contribute, in addition, to our understanding of interactions between the nervous system and the immune system, and of the potential impact of drugs of abuse on these interactions, as may occur in active drug abusers with AIDS.